The invention relates to novel compounds and pharmaceutically acceptable salts thereof, their use, either alone or in combination with other therapeutic agents, in the treatment or prophylaxis of HIV infection, and to pharmaceutical compositions comprising the compounds that are active against NNRTI resistant mutants.
The disease known as acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), particularly the strain known as HIV-1. In order for HIV to be replicated by a host cell, the information of the viral genome must be integrated into the host cell""s DNA. However, HIV is a retrovirus, meaning that its genetic information is in the form of RNA. The HIV replication cycle therefore requires a step of transcription of the viral genome (RNA) into DNA, which is the reverse of the normal chain of events. An enzyme that has been aptly dubbed reverse transcriptase (RT) accomplishes the transcription of the viral RNA into DNA. The HIV virion includes a copy of RT along with the viral RNA.
Reverse transcriptase has three known enzymatic functions; it acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA, and frees the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell""s genome by another enzyme called integrase.
Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects, as demonstrated by known RT inhibitors such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddl), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), d4T, 3TC, Nevirapine, Delavirdine, Efavirenz, Abacavir, and Tenofovir, the main drugs thus far approved for use in the treatment of AIDS.
As with any antiviral therapy, use of RT inhibitors in the treatment of AIDS eventually leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that occur in the reverse transcriptase segment of the pol gene. Several mutant strains of HIV have been characterised, and resistance to known therapeutic agents is believed to be due to mutations in the RT gene. One of the more commonly observed mutants clinically for the non-nucleoside reverse transcriptase inhibitors, is the Y181C mutant, in which a tyrosine (Y), at codon 181, has been mutated to a cysteine (C) residue. Other mutants, which emerge with increasing frequency during treatment using known antivirals, include single mutants K103N, V106A, G190A, Y188C, and P236L, and double mutants K103N/Y181C, K103N/P225H, K103N/V108I and K103N/L100I.
As antiviral use in therapy and prevention of HIV infection continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of RT, which have different patterns of effectiveness against the various resistant mutants.
Compounds having tricyclic structures, which are inhibitors of HIV-1, are described in U.S. Pat. No. 5,366,972. Other inhibitors of HIV-1 reverse transcriptase are described in Hargrave et al., J. Med Chem., 34, 2231 (1991), Cywin et al., J. Med. Chem., 41, 2972 (1998) and Klunder et al., J. Med. Chem., 41, 2960 (1998).
U.S. Pat. No. 5,705,499 proposes 8-arylalkyl- and 8-arylheteroalkyl-5,11 -dihydro-6H-dipyrido[3,2-B:2xe2x80x2,3xe2x80x2-E][1,4]diazepines as inhibitors of RT. The exemplified compounds are shown to have some activity against HIV WT reverse transcriptase.
WO 01/96338A1 discloses diazepine structures having quinoline and quinoline-N-oxide substituents as inhibitors of RT. The exemplified compounds have activity against HIV WT, single and double mutant strains.
The invention provides novel fused ring-containing compounds that are potent inhibitors of wild-type (WT) and double mutant strains of HIV-1 RT, particularly the double mutation K103N/Y181C.
In a first aspect the invention provides compounds represented by formula I: 
wherein
R2 is selected from the group consisting of H, halogen, NHNH2, (C1-4)alkyl, O(C1-6)alkyl, and haloalkyl;
R4 is H or Me;
R5 is H or (C1-4)alkyl;
R11 is (C1-4)alkyl, (C1-4)alkyl(C3-7)cycloalkyl, or (C3-7)cycloalkyl; and
Q is naphthyl, fused phenyl(C4-7)cycloalkyl and fused phenyl-5, 6, or 7-membered saturated heterocycle having one to two heteroatom selected from O, N, or S, said Q being substituted with from 1 to 4 R12 substituents selected from: R13, (C1-6)alkyl, (C3-7)cycloalkyl, or (C2-6)alkenyl, said alkyl, cycloalkyl, or alkenyl being optionally substituted with R13,
wherein R13 is defined as:
a) NR13aCOR13b wherein R13a and R13b are each independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl, said alkyl, cycloalkyl or alkyl-cycloalkyl being optionally substituted with R14;
b) NR13cSO2R13d wherein R13c is H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl and R13d is (C1-6)alkyl, haloalkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl, said alkyl, cycloalkyl or alkyl-cycloalkyl being optionally substituted with R14;
c) COR13e wherein R13e has the same definition as R13d;
d) COOR13f wherein R13f has the same definition as R13c;
e) CONR13gR13h wherein R13g and R13h are both independently H, (C1-6)alkyl, (C3-7)cycloalkyl, or (C1-6)alkyl-(C3-7)cycloalkyl; or both R13g and R13h are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle; or R13h is N(R13i)2 wherein each R13i is independently H, (C1-6)alkyl, (C3-7)cycloalkyl, or (C1-6)alkyl-(C3-7)cycloalkyl or both R13i are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl or heterocycle being optionally substituted with R14;
f) CONR13jSO2R13k wherein R13j has the same definition as R13c and R13k has the same definition as R13d; or
g) SO2R13l wherein R13l is (C1-6)alkyl, (C3-7)cycloalkyl, or (C1-6)alkyl-(C3-7)cycloalkyl; or R13l is NR13mR13n wherein R13m and R13n are both independently H, (C1-6)alkyl, (C3-7)cycloalkyl, or (C1-6)alkyl-(C3-7)cycloalkyl; or both R13m and R13n are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl or heterocycle being optionally substituted with R14;
wherein R14 is defined as:
COOR14a, or CON(R14b)2 wherein R14a and R14b are both independently H, (C1-6)alkyl, (C3-7)cycloalkyl, or (C1-6)alkyl-(C3-7)cycloalkyl; or both R14b are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle;
as well as pharmaceutically acceptable salts, esters and prodrugs thereof.
In a first subgeneric aspect the invention provides compounds represented by formula I, wherein:
R2 is selected from the group consisting of H, F, Cl, NHNH2, (C1-4 alkyl), and CF3;
R4 is H or Me;
R5 is H or Me;
R11 is (C1-4 alkyl), or (C3-7cycloalkyl); and
Q is selected from the group consisting of: 
xe2x80x83wherein
R12 is selected from the group consisting of: COOH, (C1-6 alkyl)COOH, (C2-6alkenyl)COOH, (C1-6 alkyl)COO(C1-6 alkyl), (C1-6 alkyl)CONH2, (C3-7cycloalkyl)COOH, (C1-6 alkyl)CONHNH2, CH2CONHSO2CH3, NHSO2CH3, NHSO2CF3, SO2NHCOCH3, SO2NH2, NHCO(C1-4alkyl)COOH, NHCOCH2C(CH3)2COOH, and SO2NHCH2COOH;
as well as pharmaceutically acceptable salts, esters and prodrugs thereof.
According to a second aspect of the invention, there is provided a pharmaceutical composition for the treatment or prevention of HIV infection, comprising a compound of formula I, as described herein, or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier.
According to a third aspect of the invention, there is provided a method for the treatment or prevention of HIV infection, comprising administering to a patient an HIV inhibiting amount of a compound of formula I as described herein, or a pharmaceutically acceptable salt, ester or prodrug thereof.
According to a fourth aspect of the invention, there is provided a method for the treatment or prevention of HIV infection, comprising administering to a patient an HIV inhibiting amount of a pharmaceutical composition, as described herein.
According to a fifth aspect of the invention, there is provided a method for treating or preventing HIV infection comprising administering a compound of formula I, as described herein, in combination with an antiretroviral drug.
According to a sixth aspect of the invention, there is provided a method for preventing perinatal transmission of HIV-1 from mother to baby, comprising administering a compound of formula I, as described herein, to the mother before giving birth.
Definitions
The following definitions apply unless otherwise noted: As used herein, the terms xe2x80x9c(C1-6)alkylxe2x80x9d, or xe2x80x9c(C1-4)alkylxe2x80x9d either alone or in combination with another radical, are intended to mean acyclic straight or branched chain alkyl radicals containing from one to six or from one to four carbon atoms respectively. Examples of such radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.
As used herein, the terms xe2x80x9c(C3-7)cycloalkylxe2x80x9d or xe2x80x9c(C4-7)cycloalkylxe2x80x9d are intended to mean saturated cyclic hydrocarbon radicals containing from three to seven carbon atoms or from four to seven carbon atoms respectively, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
As used herein, the term xe2x80x9c(C2-6)alkenylxe2x80x9d, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight or branched chain radical containing from two to six carbon atoms.
As used herein, the term xe2x80x9cfused phenyl(C4-7)cycloalkylxe2x80x9d, either alone or in combination with another radical, is intended to mean a phenyl that is fused with a (C4-7)cycloalkyl, as defined herein.
As used herein, the term xe2x80x9cfused phenyl-5, 6, or 7-membered saturated heterocyclexe2x80x9d, either alone or in combination with another radical is intended to mean a phenyl that is fused with a 5, 6, or 7-membered non-aromatic heterocycle having from 1 to 2 heteroatoms selected from O, N, or S. Examples include tetrahydroquinoline and tetrahydroisoquinoline.
As used herein, the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d is intended to mean a halogen atom, and includes fluorine, chlorine, or bromine.
As used herein, the term xe2x80x9chaloalkylxe2x80x9d is intended to mean an alkyl that is described above in which each hydrogen atom may be successively replaced by a halogen atom, for example CH2Br or CH2F.
As used herein, the term xe2x80x9csingle or double mutant strainsxe2x80x9d means that either one or two amino acid residues that are present in WT HIV-1 strain have been replaced by residues not found in the WT strain. For example, the single mutant Y181C is prepared by site-directed mutagenesis in which the tyrosine at residue 181 has been replaced by a cysteine residue. Similarly, for the double mutant K103N/Y181C, an asparagine residue has replaced the lysine at residue 103 and a cysteine residue has replaced the tyrosine at residue 181.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes those derived from pharmaceutically acceptable bases and is non-toxic. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na+, K+, and Ca++ salts are also contemplated to be within the scope of the invention (also see Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein by reference).
Preferably, compounds are of formula I as defined above, wherein preferably R2 is selected from the group consisting of H, Cl, F, NHNH2, CH3, and OMe. More preferably, R2 is H, Cl, F, or CH3. Most preferably, R2 is H, Cl, or F.
Preferably, R4 is H.
Preferably, R5 is Me.
Preferably, R11 is Et.
Preferably Q is naphthyl, fused phenyl(C4-7)cycloalkyl and fused phenyl-5, 6, or 7-membered saturated heterocycle having one N atom, said Q being substituted with from 1 to 4 R12 substituents.
More preferably, Q is selected from the group consisting of: naphthyl, tetrahydronaphthyl, indanyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl,
said Q being mono- or disubstituted with R12.
Preferably, R12 is (C1-6)alkyl, (C2-4)alkenyl or (C3-7)cycloalkyl, said alkyl, cycloalkyl or alkenyl being optionally substituted with R13 wherein R13 is selected from the group consisting of:
a) COOH;
b) CONR13gR13h wherein R13g and R13h are both independently H, or (C1-6)alkyl optionally substituted with COOH; or R13h is NH2; and
c) CONHSO2CH3;
or R12 is:
a) NHCO(C1-6)alkyl-COOH;
b) NHSO2CH3 or NHSO2CF3;
c) COCH3 or COCH2COOH;
d) COOR13f wherein R13f is H or (C1-6)alkyl;
e) CONR13gR13h wherein R13g and R13h are both independently H, or (C1-6)alkyl optionally substituted with COOH; or R13h is NH2;
f) CONHSO2CH3; or
g) SO2Me, SO2NH2, SO2NHCOCH3, SO2NHCH2COOH, or SO2N(CH3)2.
More preferably R12 is CH3, CH2COOH, (CH2)2COOH, CH(Me)COOH, CH(Me)CH2COOH, CH2CH(Me)COOH, CH2CONH2, CH2CONHNH2, CH2CH2CONHNH2, CH2CONHSO2Me, 
COOH, COOMe, COO-t-Bu, COMe, COCH2COOH, CONHC(Me)2COOH, CONHNH2, CONHEt, CONMe2, NHCO(CH2)2COOH, NHCOCH2C(Me)2COOH, NHSO2CF3, NHSO2Me, SO2Me, SO2NMe2, SO2NH2, SO2NHAc, or SO2NHCH2COOH.
Even more preferably R12 is CH3, CH2COOH, (CH2)2COOH, CH2CONH2, CH2CONHNH2, 
COOH, COOMe, COO-t-Bu, COMe, CONMe2, NHSO2Me, SO2Me, SO2NMe2, SO2NH2, or SO2NHCH2COOH.
Most preferably, R12 is CH2CONH2, CH2CONHNH2, COOH, CONMe2, NHSO2Me, SO2Me, SO2NMe2, SO2NH2, or SO2NHCH2COOH.
Preferably, Q is 
wherein, preferably R12 is (C1-6)alkyl, (C2-4)alkenyl or (C3-7)cycloalkyl, said alkyl, cycloalkyl or alkenyl being optionally substituted with R13 wherein R13 is selected from the group consisting of:
a) COOH;
b) CONH2:
c) CONHNH2; and
d) CONHSO2CH3;
or R12 is COOH.
More preferably, R12 is CH2COOH, (CH2)2COOH, CH(Me)COOH, CH(Me)CH2COOH, CH2CH(Me)COOH, CH2CONH2, CH2CONHNH2, CH2CONHSO2Me, 
or COOH.
Even more preferably, R12 is CH2COOH, (CH2)2COOH, CH2CH(Me)COOH, CH2CONH2, CH2CONHNH2, 
or COOH.
Most preferably, R12 is CH2COOH, (CH2)2COOH, CH2CH(Me)COOH, CH2CONH2, CH2CONHNH2, or COOH.
Alternatively preferably, Q is 
wherein preferably, R12 is (C1-6)alkyl, or (C2-4)alkenyl, said alkyl or alkenyl being optionally substituted with R13 wherein R13 is selected from the group consisting of:
a) COOH;
b) CONHNH2; and
c) CONHSO2CH3;
or R12 is:
a) NHCO(C1-6)alkyl-COOH;
b) NHSO2CH3 or NHSO2CF3;
c) COOH; or
d) SO2NH2, SO2NHCOCH3, or SO2NHCH2COOH.
More preferably, R12 is CH2COOH, (CH2)2COOH, CH2CH(Me)COOH, CH2CH2CONHNH2, CH2CONHSO2Me, 
COOH, NHCO(CH2)2COOH, NHCOCH2C(Me)2COOH, NHSO2CF3, NHSO2Me, SO2NH2, SO2NHAc, or SO2NHCH2COOH.
Even more preferably, R12 is 
NHSO2Me, SO2NH2, SO2NHCH2COOH, or (CH2)2COOH.
Most preferably, R12 is NHSO2Me, SO2NH2, SO2NHCH2COOH, or (CH2)2COOH.
Alternatively preferably, Q is 
wherein preferably R12b is (C1-6)alkyl substituted with R13 wherein R13 is selected from the group consisting of:
a) COOH; and
b) CONHNH2;
or R12b is:
a) COOH;
b) CONHNH2 or CONHC(Me)2COOH;
and preferably R12a is H or CH3.
More preferably, R12b is CH2COOH and more preferably, R12a is CH3.
Alternatively preferably, Q is 
Alternatively preferably, Q is 
wherein preferably R12 is (C1-6)alkyl substituted with COOH or R12 is COOH.
More preferably, R12 is CH2COOH, CH2CH2COOH or COOH.
Alternatively preferably, Q is 
wherein preferably R12 is CH2COOH or COCH2COOH.
Alternatively preferably, Q is 
wherein preferably, R12 is
a) COCH3;
b) COO(C1-6)alkyl;
c) CONHEt, CONMe2; or
d) SO2Me or SO2N(CH3)2.
More preferably, R12 is COMe, CONMe2, COOMe, COOtBU, SO2Me, or SO2NMe2.
Most preferably, R12 is CONMe2, COOMe, COOtBU, or SO2NMe2.
Specific Embodiments
Included within the scope of this invention are all compounds of formula I as presented in Tables 1 to 7.
The compounds of formula I are effective inhibitors of wild type HIV as well as inhibiting the double mutant enzyme K103N/Y181C. The compounds of the invention may also inhibit the single mutant enzymes V106A, Y188L, K103N, Y181C, P236L and G190A. The compounds may also inhibit other double mutant enzymes including K103N/P225H, K103N/V108I and K103N/L100I.
The compounds of formula I possess inhibitory activity against HIV-1 replication. When administered in suitable dosage forms, they are useful in the treatment of AIDS, ARC and related disorders associated with HIV-1 infection. Another aspect of the invention, therefore, is a method for treating HIV-1 infection which comprises administering to a human being, infected by HIV-1, a therapeutically effective amount of a novel compound of formula I, as described above. Whether it is termed treatment or prophylaxis, the compounds may also be used to prevent perinatal transmission of HIV-1 from mother to baby, by administration to the mother before giving birth.
The compounds of formula I may be administered in single or divided doses by the oral, parenteral or topical routes. A suitable oral dosage for a compound of formula I would be in the range of about 0.5 mg to 3 g per day. A preferred oral dosage for a compound of formula I would be in the range of about 100 mg to 800 mg per day for a patient weighing 70 kg. In parenteral formulations, a suitable dosage unit may contain from 0.1 to 250 mg of said compounds, preferably 1 mg to 200 mg, whereas for topical administration, formulations containing 0.01 to 1% active ingredient are preferred. It should be understood, however, that the dosage administration from patient to patient would vary. The dosage for any particular patient will depend upon the clinician""s judgement, who will use as criteria for fixing a proper dosage the size and condition of the patient as well as the patient""s response to the drug.
When the compounds of the present invention are to be administered by the oral route, they may be administered as medicaments in the form of pharmaceutical preparations that contain them in association with a compatible pharmaceutical carrier material. Such carrier material can be an inert organic or inorganic carrier material suitable for oral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene-glycols, petroleum jelly and the like.
The compounds of formula I can be used in combination with an antiretroviral drug known to one skilled in the art, as a combined preparation useful for simultaneous, separate or sequential administration for treating or preventing HIV infection in an individual. Examples of antiretroviral drugs that may be used in combination therapy with compounds of formula I, include but are not limited to, NRTIs (such as AZT), NNRTI""s (such as Nevirapine), reverse transcriptase inhibitors (such as zidovudine and abacavir), CCR5 antagonists (such as TAK-779), CXCR4 antagonists (such as AMD-3100), integrase inhibitors, viral fusion inhibitors (such as T-20), antifungal or antibacterial agents (such as fluconazole), compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type, compounds of the xcex1-APA (xcex1-anilino phenyl acetamide)-type, TAT inhibitors, protease inhibitors (such as Ritanovir), immunomodulating agents (such as Levamisole) and investigational drugs (such as DMP-450 or DPC-083). Moreover, a compound of formula I can be used with another compound of formula I.
The pharmaceutical preparations can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilization. Further, the pharmaceutical preparations may contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, flavor-improvers, wetting agents, buffers, salts for varying the osmotic pressure and the like. Solid carrier material which can be used include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).
For parenteral use, a compound of formula I can be administered in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides. Preservatives may also be added if necessary, such as benzoic acid, methyl or propyl paraben, benzalkonium chloride and other quaternary ammonium compounds.
The compounds of this invention may also be administered as solutions for nasal application and may contain in addition to the compounds of this invention suitable buffers, tonicity adjusters, microbial preservatives, antioxidants and viscosity-increasing agents in an aqueous vehicle. Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin. Microbial preservatives added may include benzalkonium chloride, thimerosal, chloro-butanol or phenylethyl alcohol.
Additionally, the compounds provided by the invention may be administerable by suppository.
Methodology and Synthesis
Exemplary reaction schemes, disclosed in WO 01/96338A1, the contents of which are incorporated herein by reference, show the many synthetic routes to the tricyclic compounds illustrated hereinafter. The compounds of the present invention may be made using the skills of a synthetic organic chemist. Exemplary reaction schemes are illustrated in Schemes 1 to 4. Substituents R2, R4, R5, R11, and R12 are as defined herein. 
Briefly, using a Mitsunobu-type reaction, naphthyl derivatives 1(ii), 1(iii) or 1(iv) when Y is R12 with the exception of COOH, are condensed with 1(i) to produce compounds of formula I. Alternatively, when Y is a R12 group precursor, for example COOCH3, a Mitsunobu-type reaction can be used to condense 1(iv) or 1(iii) with 1(i), and thereafter Y can be chemically converted into R12 substituents, for example by saponification of COOCH3 to give COOH, thereby giving compounds of formula I. Other methods of condensation to produce the ether linkage in compounds of formula I are also contemplated, for example an SN2 displacement of a suitably derivatized primary alcohol in 1(i) by 1(ii), 1(iii) or 1(iv). 
Referring to Scheme 2 above, naphthyl derivatives 2(i), 2(ii), and 2(iii), in which Y is a precursor of R12, for example COOCH3, and W is a hydroxyl-protecting group, Y is chemically converted to R12, for example by reacting COOCH3 with hydrazine to give CONHNH2Removal of W using art-recognized chemistry (see xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Theodora W. Greene and Peter G. M. Wuts, second edition, 1991) produces a phenolic derivative, which thereafter is condensed with 1(i) using a Mitsunobu-type condensation, to produce compounds of formula I. 
Referring to Scheme 3 above, naphthyl derivatives 3(i), 3(ii), and 3(iii), where Y is a precursor of R12, for example COOCH3 and W is a hydroxyl-protecting group, W is removed using art-recognized chemistry (see xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Theodora W. Greene and Peter G. M. Wuts, second edition, 1991). This produces a phenolic derivative, which is condensed with 1(i) using a Mitsunobu-type condensation, followed thereafter by a chemical conversion of Y to R12 for example saponification of COOCH3 to give COOH, to produce compounds of formula I. 
As stated before, the compounds provided by the invention inhibit the enzymatic activity of HIV-1 RT. Based upon testing of these compounds, as described below, it is known that they inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT. It is known (data not shown) that they also inhibit the DNA-dependent DNA polymerase activity of HIV-1 RT. Utilising the Reverse Transcriptase (RT) Assay described below, compounds can be tested for their ability to inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT. Certain specific compounds described in the Examples which appear below, were so tested. The results of this testing appear in Table 4 as IC50 (nM) and Table 5 as EC50 (nM).